PT  - JOURNAL ARTICLE
AU  - Safrany, S T
AU  - Wojcikiewicz, R J
AU  - Strupish, J
AU  - McBain, J
AU  - Cooke, A M
AU  - Potter, B V
AU  - Nahorski, S R
TI  - Synthetic phosphorothioate-containing analogues of inositol 1,4,5-trisphosphate mobilize intracellular Ca2+ stores and interact differentially with inositol 1,4,5-trisphosphate 5-phosphatase and 3-kinase.
DP  - 1991 Jun 01
TA  - Molecular Pharmacology
PG  - 754--761
VI  - 39
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/39/6/754.short
4100  - http://molpharm.aspetjournals.org/content/39/6/754.full
SO  - Mol Pharmacol1991 Jun 01; 39
AB  - Intracellular Ca2+ stores in permeabilized SH-SY5Y neuroblastoma cells were mobilized by D-myo-inositol 1,4,5-trisphosphate [D-Ins(1,4,5)P3] and two of its synthetic analogues, DL-myo-inositol 1,4-bisphosphate 5-phosphorothioate (DL-InsP3-5S) and DL-myo-inositol 1,4,5-trisphosphorothioate (DL-InsP3S3). The concentrations of D-Ins(1,4,5)P3, DL-InsP3-5S, and DL-InsP3S3 required for half-maximal release were 0.11, 0.8, and 2.5 microM, respectively. All agents were full agonists, releasing 55-60% of sequestered 45Ca2+. D-Ins(1,4,5)P3-induced mobilization of Ca2+ was transient, and Ca2+ reuptake followed D-Ins(1,4,5)P3 metabolism closely. DL-InsP3S3-induced mobilization was persistent, consistent with the resistance of this analogue to metabolic enzymes. In contrast, DL-InsP3-5S-induced Ca2+ mobilization was followed by reuptake of Ca2+, albeit at a slower rate than that seen with D-Ins(1,4,5)P3. DL-InsP3-5S and DL-InsP3S3 were resistant to D-Ins(1,4,5)P3 5-phosphatase and potently inhibited the enzyme, with Ki values of 6.8 and 1.7 microM, respectively. DL-InsP3S3 was resistant to D-Ins(1,4,5)P3 3-kinase and was a very weak inhibitor of the enzyme (Ki = 230 microM). The ability of DL-InsP3-5S to inhibit D-Ins(1,4,5)P3 phosphorylation (apparent Ki = 5 microM) and its loss of Ca(2+)-releasing ability on incubation with D-Ins(1,4,5)P3 3-kinase suggest that this analogue may undergo phosphorylation to inositol 1,3,4-trisphosphate 5-phosphorothioate. These differential and complementary properties of DL-InsP3-5S and DL-InsP3S3 may be useful in dissecting the roles of D-Ins(1,4,5)P3 and D-myo-inositol 1,3,4,5-tetrakisphosphate in Ca2+ homeostasis.